The present invention relates to substituted bicyclic imidazo-3-yl-amines and medicaments comprising these compounds.
Interesting pharmacological properties are known for individual compounds from the class of imidazo-3-yl-amines. Thus, certain imidazo[1,2-a]pyridines are known as active compounds which lower blood pressure (GB-B-1,135,893), as anthelmintics and antimycotics (J. Med. Chem. 1972, 15, 982-985), and as antisclerotic active compounds for the treatment of inflammatory diseases (EP-A-0 068 378). EP-A-0 266 890 and J. Med. Chem. 1987, 30, 2031-2046 also describe an action of individual imidazopyridines against inflammatory diseases, in particular of the stomach. Further pharmacological actions described for individual representatives from the class of imidazo-3-yl-amines are antibacterial properties (Chem. Pharm. Bull. 1992, 40, 1170), antiviral properties (J. Med. Chem. 1998, 41, 5108-5112) and the action as a benzodiazepine receptor antagonist (J. Heterocyclic Chem. 1998, 35, 1205-1217).
In view of these interesting actions, various representatives from the class of substituted imidazo-3-yl-amines have been synthesized in the past. In particular, attempts have been made to increase the number of substituted imidazo-3-yl-amines available by combinatory synthesis processes. Thus, C. Blackburn et al. describe a three-component solid phase synthesis for the preparation of imidazo-3-yl-amines in Tetrahedron Lett. 1998, 39, 5469-5472 and a three-component condensation for parallel synthesis of imidazo-3-yl-amines in Tetrahedron Lett. 1998, 39, 3635-3638. The synthesis published by K. Groebke et al. in Synlett 1998, 661-663 is similar to the latter reaction. A multi-component reaction for combinatory synthesis of imidazo-3-yl-amines, with which individual imidazo-5-amines have also been prepared, is also described by H. Bienayme and K. Bouzid in Angew. Chem. 1998, 110 (16), 2349-2352.
However, the range of variation possible according to the prior art for the substituents on the amino nitrogen and in the 2-position of the imidazole ring was limited.
The present invention was therefore based on the object of providing further bicyclic imidazo-3-yl-amines, and medicaments comprising these compounds.
The invention therefore provides bicyclic imidazo-3-yl-amines of general formula I 
wherein
X and Y denote CH or N, with the proviso that X and Y do not simultaneously denote N,
R1 denotes tert-butyl, (CH2)nCN, where n=4, 5 or 6, optionally substituted phenyl, C4-C8-cycloalkyl, CH2CH2R (R=4-morpholino), 1,1,3,3-tetramethylbutyl or CH2Ra, wherein Ra represents hydrogen, OH, C1-C8-alkyl (branched or unbranched), optionally substituted phenyl, CO(ORxe2x80x2) (where Rxe2x80x2=unbranched C1-C4-alkyl or branched C1-C5-alkyl), PO(ORxe2x80x2)2 (where Rxe2x80x2=unbranched C1-C4-alkyl or branched C1-C5-alkyl) or Si(RxRyRz) (where Rx, Ry, and Rz in each case independently of one another are C1-C4-alkyl (branched or unbranched), C4-C8-cycloalkyl or phenyl);
R2 denotes hydrogen, CORb, wherein Rb represents C1-C4-alkyl (branched or unbranched) or C3-C8-cycloalkyl, CH2CH2CO(ORc), wherein Rc represents C1-C4-alkyl (branched or unbranched), adamantyl, optionally substituted phenyl, optionally substituted 1-naphthyl or 2-naphthyl or in each case optionally substituted 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl or furoyl, CH2-phenyl, CH2CH2Rd, wherein Rd represents optionally substituted phenyl, or CONHRe, wherein Re represents C1-C8-alkyl (branched or unbranched), C3-C8-cycloalkyl or optionally substituted phenyl;
R3 denotes methyl, ethyl, tert-butyl, C3-C8-cycloalkyl, phenyl, optionally monosubstituted in the 3-, 5- or 6-position or optionally polysubstituted in the 4-position and additionally in the 2- and/or 3- and/or 5- and/or 6-position, phenoxy, optionally substituted naphthyl, optionally substituted pyrrole, optionally substituted pyridyl, optionally substituted furan, optionally substituted thiophene, optionally substituted anthracene, optionally substituted phenanthrene or optionally substituted quinoline,
with the proviso that R3 does not denote n-propyl, cyclohexyl, unsubstituted phenyl or phenyl monosubstituted in the 3-position with a carboxylic acid amide group if R1 denotes t-butyl, n-propyl, n-butyl, 1,1,3,3-tetramethylbutyl, cyclohexyl, CH2CH2R (R=4-morpholino), monosubstituted phenyl, 2,6-dimethylphenyl or benzyl and at the same time R2 denotes hydrogen or xe2x80x94CO(methyl), and that R2 does not denote hydrogen if at the same time R1 denotes benzyl and R3 denotes methyl, or at the same time R1 denotes CH2C(O)tert-butyl and R3 denotes unsubstituted phenyl; in the form of at least one base or of at least one pharmaceutically acceptable salt.
Preferred compounds according to the invention are those in which R2 denotes hydrogen; R1 is selected from the group consisting of (CH2)nCN, where n=4, 5 or 6, cyclohexyl, CH2CO(O-methyl), 2,6-dimethylphenyl, 1,1,3,3-tetramethylbutyl, tert-butyl or n-butyl; and R3 is selected from the group consisting of 2-pyridyl, 3-pyridyl, 2-furanyl, 2-pyrroyl, methyl, tert-butyl, 3-hydroxyphenyl, 3,4-dimethoxyphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 3-bromophenyl, 4-bromo-2-fluorophenyl, 5-bromo-2-fluorophenyl, 3-bromo-4-fluorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl, 3-fluorophenyl, 3-methylphenyl, 3-phenoxyphenyl, 3-(4-chlorophenoxy)phenyl, 2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2-bromophenyl, 2-fluorophenyl, or 2-(trifluoromethyl)-phenyl.
Compounds which are particularly preferred according to the invention are bicyclic imidazo-3-yl-amines selected from the group consisting of
(6-isocyano-hexyl)-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-(6-isocyano-hexyl)-amine,
(2-cyclohexyl-imidazo[1,2-a]pyrazin-3-yl)-(6-isocyano-hexyl)-amine,
(2,6-dimethyl-phenyl)-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
(2-furan-2-yl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester,
(2-cyclohexyl-imidazo[1,2-a]pyrimidin-3-ylamino)-acetic acid methyl ester,
(2-methyl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester,
(2-pyridin-4-yl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine,
(2-methyl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine,
3-(3-tert-butylamino-imidazo[1,2-a]pyridin-2-yl)-phenol, butyl-[2-(2,3-dichloro-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-amine,
[(2-phenyl-imidazo[1,2-a]pyridin-3-ylamino)-methyl]-phosphonic acid diethyl ester,
tert-butyl-(2-tert-butyl-imidazo [1,2-a]pyridin-3-yl)-amine,
butyl-(2-o-tolyl-imidazo [1,2-a]pyrimidin-3-yl)-amine,
(2,6-dimethyl-phenyl)-[2-(2-methoxy-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-amine,
butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine,
tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyrimidin-3-yl)-amine,
tert-butyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine,
[2-(1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
cyclohexyl-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
cyclohexyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine,
N-cyclohexyl-N-[2-(5-methyl-furan-2-yl)-imidazo[1,2-a]pyridin-3-yl]-acetamide,
tert-butyl-[2-(5-methylsulfanyl-thiophen-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-amine,
[2-(3-bromo-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl]-cyclohexyl-amine, acetic acid 2-methoxy-4-[3-(1,1,3,3-tetramethyl-butylamino)-imidazo[1,2-a]pyrimidin-2-yl]-phenyl ester,
[2-(2-chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-3-yl]-(1,1,3,3-tetramethylbutyl)-amine,
(2-anthracen-9-yl-imidazo[1,2-a]pyrazin-3-yl)-tert-butyl-amine,
tert-butyl-(2-naphthalen-1-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
N-cyclohexyl-N-[2-(4,5-dimethyl-furan-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-acetamide, or
(1,1,3,3-tetramethylbutyl)-[2-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-a]pyridin-3-yl]-amine.
If the bicyclic imidazo-3-yl-amines according to the invention contain optically active carbon atoms, the present invention also provides the enantiomers of these compounds and mixtures thereof.
The invention furthermore provides medicaments comprising as the active compound at least one bicyclic imidazo-3-yl-amine of general formula I, in which R1 to R3, X and Y have the abovementioned meanings, in the form of 2 base or of 2 pharmaceutically acceptable salt, preferably of hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, and/or aspartic acid, or, in particular, of hydrochloric acid.
Surprisingly, it has been found that compounds according to the invention not only are potential active compounds for the indications previously known, but also show analgesic action.
A medicament according to the invention particularly preferably comprises as an active compound at least one bicyclic imidazo-3-yl-amine selected from the group consisting of
(6-isocyano-hexyl)-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-(6-isocyano-hexyl)-amine,
2-cyclohexyl-imidazo[1,2-a]pyrazin-3-yl)-(6-isocyano-hexyl)-amine,
2,6-dimethyl-phenyl)-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
2-furan-2-yl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester,
2-cyclohexyl-imidazo[1,2-a]pyrimidin-3-ylamino)-acetic acid methyl ester,
2-methyl-imidazo[1,2-a]pyrazin-3-ylamino)-acetic acid methyl ester,
2-pyridin-4-yl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine,
2-methyl-imidazo[1,2-a]pyrazin-3-yl)-(1,1,3,3-tetramethyl-butyl)-amine,
3-(3-tert-butylamino-imidazo[1,2-a]pyridin-2-yl)-phenol,
butyl-[2-(2,3-dichloro-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-amine,
[(2-phenyl-imidazo[1,2-a]pyridin-3-ylamino)-methyl]-phosphonic acid diethyl ester,
tert-butyl-(2-tert-butyl-imidazo[1,2-a]pyridin-3-yl)-amine,
butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine,
2,6-dimethyl-phenyl)-[2-(2-methoxy-phenyl)-imidazo[1,2-a]pyrazin-3-yl]-amine,
butyl-(2-o-tolyl-imidazo[1,2-a]pyrimidin-3-yl)-amine,
tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyrimidin-3-yl)-amine,
tert-butyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine,
[2-(1H-pyrrol-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-(1,1,3,3-tetramethyl-butyl)-amine,
cyclohexyl-(2-furan-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-pyridin-3-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-pyridin-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
tert-butyl-(2-thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
cyclohexyl-(2-methyl-imidazo[1,2-a]pyridin-3-yl)-amine,
N-cyclohexyl-N-[2-(5-methyl-furan-2-yl)-imidazo[1,2-a]pyridin-3-yl]-acetamide,
tert-butyl-[2-(5-methylsulfanyl-thiophen-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-amine,
[2-(3-bromo-thiophen-2-yl)-imidazo[1,2-a]pyridin-3-yl]-cyclohexyl-amine, acetic acid 2-methoxy-4-[3-(1,1,3,3-tetramethyl-butylamino)-imidazo[1,2-a]pyrimidin-2-yl]-phenyl ester,
[2-(2-chloro-4-fluoro-phenyl)-imidazo[1,2-a]pyrimidin-3-yl]-(1,1,3,3-tetramethylbutyl)-amine,
2-anthracen-9-yl-imidazo[1,2-a]pyrazin-3-yl)-tert-butyl-amine,
tert-butyl-(2-naphthalen-1-yl-imidazo[1,2-a]pyridin-3-yl)-amine,
N-cyclohexyl-N-[2-(4,5-dimethyl-furan-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-acetamide, or
(1,1,3,3-tetramethylbutyl)-[2-(3,4,5-trimethoxy-phenyl)-imidazo[1,2-a]pyridin-3-yl]-amine, or the pharmaceutically acceptable salts of these compounds.
A particulary preferred embodiment of the present invention is a use of a bicyclic imidazo-3-yl-amine according to the invention, together with one or more auxiliary substances, for the preparation of a medicament for combating pain. Methods of treating pain in a patient in need thereof are also an embodiment of the present invention.
For the preparation of an appropriate medicament, in addition to at least one active compound according to the invention, one or more auxiliary substances, preferably at least one of carrier materials, fillers, solvents, diluents, dyestuffs and/or binders, are employed. The choice of auxiliary substances and the amounts thereof to be employed depend on whether the medicament is to be administered orally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally or locally. Formulations in the form of tablets, coated tablets, capsules, granules, drops, juices, and syrups are suitable for oral administration, and solutions, suspensions, easily reconstitutable dry formulations, and sprays are suitable for parenteral, topical and inhalatory administration. Active compounds according to the invention in a depot, in dissolved form or in a patch, optionally with the addition of agents which promote penetration through the skin, are suitable formulations for percutaneous administration. Formulation forms which can be used orally or percutaneously can release the active compounds according to the invention in a retarded manner.
The amount of active compound to be administered to the patient varies according to the weight of the patient and to the mode of administration, as well as to the indication and the severity of the disease.
The compounds according to the invention are synthesized by a procedure in which amidines with general formula II, particularly 2-aminopyridine, 2-aminopyrazine and 2-aminopyrimidine derivatives (commercially available from companies such as Acros, Avocado, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma or TCI-Jp), are reacted with varous ketones or, preferably, aldehydes III and isonitriles IV in the presence of 20% perchloric acid in accordance with a three-component reaction. R1 to R3, X and Y here have the meanings given above for compounds of the formula I. 
For a problem-free course of the reaction, the starting compounds are added successively in the sequence amidine II, aldehyde III, and isonitrile IV. The reactions are preferably carried out in methylene chloride at a temperature of preferably 0xc2x0 C. to 40xc2x0 C., in particular at a temperature of 10xc2x0 C. to 20xc2x0 C.
To prepare the compounds according to the invention in which R2 does not denote hydrogen, the compounds Ia formed in the reaction described above, which have preferably first been dissolved in THF, are reacted, depending on the desired end product, with a compound R2Hal, wherein Hal represents bromine, iodine or, particularly, chlorine, for example an optionally substituted alkyl, aryl or acid chloride, or an optionally substituted isocyanate ReNCO in the presence of a morpholine resin (e.g., polystyrene-morpholine from Argonaut) in methylene chloride in the course of 2 to 24 hours at temperatures between 10xc2x0 C. and 40xc2x0 C. in accordance with the following equation: 
The excess reagents are then removed from the reaction mixtures by filtration over a layer with polymer-bonded tris(2-aminoethyl)amine (manufacturer: Novabiochem) or 3-(3-mercaptophenyl)propanamidomethylpolystyrene and the filtrate is concentrated, for example, in a vacuum centrifuge. The entire process can also easily be carried out in an automated synthesis unit.
The compounds of the formula I can be converted into their salts in a known manner with physiologically tolerated acids, preferably hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, and/or aspartic acid, and particularly hydrochloric acid. The salt formation is preferably carried out in a solvent, preferably diethyl ether, diisopropyl ether, acetic acid alkyl esters, acetone, or 2-butanone, or in a mixture of these solvents. Alternatively, trimethylsilane in aqueous solution is also suitable for preparation of the hydrochlorides.